Surface modified polymer beads

ABSTRACT

A polymeric resin is disclosed in the form of beads or particles having a coating thereon which renders the resin blood compatible. The resin comprises divinylbenzene monomer which has a porosity, pore size, and surface area suitable for absorbtion of unhealthy components of blood, such as β-2-microglobulin.

This application is a abandoned Continuation of prior application Ser.No. 09/236,153, filed Jan. 22, 1990.

BACKGROUND OF THE INVENTION

The present invention relates to adsorbents for removing toxicants fromblood or plasma, and also for a method of producing such adsorbents.

Conventional procedures for the purification of blood extracorporeallyinclude membrane techniques (hemodialysis, plasmapheresis,ultrafiltration), sorption techniques (hemoperfusion, plasma perfusion)and combinations of these methods. Hemodialysis, ultrafiltration andplasma pheresis separate compounds according to their size and do notselectively remove specified components. Sorption techniques, on thecontrary, can be both selective and non-selective.

Hemoperfusion involves the passage of the contaminated blood over asolid surface of a detoxicant particulate mass that separates thecontaminant by sorption or by ion exchange. Another procedure, plasmaperfusion, involves separation of blood cells prior to contacting plasmawith the adsorbent. In any case, treated blood, or both cells andtreated plasma, have to be returned to the patient's blood circulationsystem.

There are cases where the toxic components to be removed from blood arewell established. In these cases, selective adsorbents can be employedwhich incorporate ligands specially designed to attract and bind thetarget species. Exemplary of potential applications of selectiveperfusion systems are: (1) the removal of autoimmune antibodies,immunoglobulins and immune complexes using adsorbents such as Protein-A;(2) removal of circulating toxins and tumor antigens (e.g.,a-fetoprotein associated with hepatic cancer, carcinoembrionic antigenassociated with various carcinomas, thioesterase or cytokeratinsassociated with breast cancer, and the like) using adsorbents such asimmobilized monoclonal antibodies and specific immobilized ligands; (3)removal of protein bound toxins and drugs (e.g., in the case ofpsychotomimetic or narcotic drug overdose) based on the antigenicproperties of these protein conjugates; (4) procedures using live cellsin the plasma chamber in the place of adsorbents such as islet cells orliver tissue fragments for the treatment of diabetes, hepatocytes forthe treatment of hepatic failure and the like; (5) selective removal ofplasma components using immobilized enzymes as adsorbents; (6) removalof cholesterol [low density lipoproteins (LDL)] using adsorbentsspecific to LDL; (7) removal of excess phosphate on the MgO/TiO complexdeposited on active carbons; (8) adsorption of triglycerides,cholesterol and fatty acids on hydrophobic polymer materials; (9)removal of human immunodeficiency virus using calcinatedhydroxyapatite-silica-alumina adsorbing materials; (10) absorbing freehemoglobin from plasma on polyphenylalanine, polyalkylene-oxide ormineral or polymeric porous materials bearing groups of tyramine,tyrosine, phenylalanine and aminophenol on the surface.

Not less frequent are cases where several toxic compounds appear inblood simultaneously, often unidentified or even unknown. These aremainly toxins of low or middle-range molecular weights. Here, selectiveimmunoadsorbents can not be prepared in a reasonable period of time andnon-selective adsorbents are needed which readily adsorb a variety ofrelatively small toxic molecules. Preferential adsorption is mainlycaused by smaller polarity of these toxins as compared to that ofnatural amino acids and saccharides which are useful conventional smallcomponents of normal blood. Hydrophobic adsorbing materials, inparticular activated carbon, are used as the non-selective adsorbents inthese cases.

Hemoperfusion and plasma perfusion on non-specific activated carbon-typesorbents was shown to be helpful in treatment of schizophrenia (Kinney,U.S. Pat. No. 4,300,551, 1981), pulmonary hypertension (SU 1507-397-A,1989), multiple sclerosis (SU 1466-754-A, 1989), treatment ofrhesus-conflict in obstetrics (SU 1533-697-A, 1989), for detoxication oforganism of patients who have undergone extensive surgery (SU1487-909-A, 1989).

A technique for cancer treatment is described by Bodden (U.S. Pat. No.5,069,662, December 1991), by which high concentrations of anti-canceragents can be perfused through a body organ containing a tumor and thenremoved from the organ with effluent blood. The contaminated blood isthen transported to an extracorporeal circuit, purified fromcontaminations and returned to the body. This permits safe infusion ofgreater than usual concentrations of chemotherapeutic agents anddelivering lethal doses of the agents to the tumor while preventingtoxic levels of the agents from entering the body's general circulation.The process is applicable to the treatment of a number of tumors such asthose of kidney, pancreas, bladder, pelvis and, in particular, theliver. Illustrative of suitable chemotherapeutic agents for use in thepractice are Adriamycin (doxorubicin), fluorinated pyrimidines(5-fluorouracyl 5-FU or floxuridine FURD), cisplatin, Mytomycin C,cyclophosphamide, methotrexate, vincristine, Bleomycin, FAMT, and anyother anti-cancer agent. Blood detoxication most effectively can beachieved by hemoperfusion through a cartridge with a non-specificsorbent, for example, activated carbon, able to clear the blood from theabove antineoplastic agents.

In a hemoperfusion system, whole blood comes into direct contact withthe sorbent, such as active carbon, which leads to two kinds of seriousproblems: first, fine carbon particles tend to be released into theblood stream to become emboli in blood vessels and organs such as lungs,spleen and kidneys; second, the biological defense system of blood maybe activated and react in several ways: the blood may coagulate to forma clot, or thrombus, the immune system may respond unfavorably, andwhite blood cells may act to encapsulate the artificial device.

Therefore, many attempts have been done to prevent release of fines andto enhance the biocompatibility of the sorbents. Clark (U.S. Pat. No.4,048,064, September 1977) describes formation of a semipermeablepolymeric coating on the carbon particles by polymerization of varioushydrophilic monomers, in particular hydroxyethylmethacrylate (HEMA) andacrylamide. Moreover, he includes heparin into the coating polymer, inorder to minimize complement activation and aggregation of platelets.Nakashima, et al. (U.S. Pat. No. 4,171,283, October 1979) suggests toadd an epoxy moiety containing comonomer, which allows post-crosslinkingof the polymeric coat formed, thus enhancing the mechanical stability ofthe coating. However, thin hydrophilic polymeric coatings were found to“fall apart”, whereas thick coatings retarded diffusion and deterioratedsorption properties of the carbon.

Maxid discloses (U.S. Pat. No. 5,149,425, September 1992; U.S. Pat. No.5,420,601, August 1993), thin integral membranes on the surface of theadsorbent can be better prepared from hydrophobic, insoluble in waterpolymer, in turn coated by a second, but water-soluble polymer.

Alternatively, activated carbon was coated with a polyelectrolytecomplex prepared from a polycation (DEAE-cellulose) and heparin andprecipitated on the surface of carbon beads (Valueva, et al., SU844-569, 1981).

Polymeric hydrophobic materials may serve as non-selective adsorbents.Endotoxins were observed to adsorb on porous polypropylene andpolyethylene (Harris, U.S. Pat. No. 4,059,512, November 1977).Macroporous styrene-divinylbenzene copolymers were shown to be usefulfor blood detoxication from barbiturates and glutethimides (Kunin, etal., U.S. Pat. No. 3,794,584, February 1974).

Polystyrene polymers prepared by an extensive cross-linking ofpolystyrene chains with rigid bi-functional cross-linking reagents suchas dichlorodimethyl ether are taught by U.S. Pat. No. 5,773,384.

While polystyrene-type adsorbents are useful to adsorb small andmiddle-size organic molecules, the hemocompatibility of the materialrequired additional improvement. An effort to render such adsorbentshemocompatible is taught in WO 97/35660, or U.S. Pat. No. 5,773,384.

The foregoing efforts are not efficient means of preparing sufficientquantities of hemocompatible absorbent resin as the cross-linkedadsorbents contain from 0.5 to 7 percent by weight of unreactedchloromethyl groups (U.S. Pat. No. 5,773,384, Col. 6, Line 52).

U.S. Pat. No. 5,051,185 discloses a double-layered structure comprisinga water-insoluble core coated with a blood compatible polymer. As awater-insoluble core there is disclosed a spherical or particulatepolymer having a particle size from 25 to 2500 μm having a specificsurface area from 5 to 55 m²/g. The water-insoluble core is preferablyporous, displaying an average pore size of from 20 to 5,000Å.

The present invention has as an objective to provide an adsorbent forremoving toxicants from blood or plasma, which is renderedhemocompatible through reaction of hemocompatible monomers or polymerswith pendant vinyl groups on the adsorbent resin. The resin may beshaped to a convenient physical dimension for use. Bead form and fiberform are physical shapes convenient for exposure to blood or plasma forremoval from blood of an absorbable component thereof.

In keeping with these objects and with others which will become apparenthereinafter, one feature of the present invention resides, in anadsorbent for removing toxicants from blood or plasma, of resin preparedfrom monomeric reactants of aromatic compounds, which resin has asurface and pore structure modified so as to prevent adsorption of largeproteins and platelets and to minimize activation of blood complementsystem, without affecting noticeably the accessibility of the inneradsorption space of the beads for small and middle-size toxicantmolecules.

It is another feature of the present invention to provide a method ofproducing the new adsorbent, which includes coating of the surface ofthe beads, particles, spheres, fiber or other convenient shape forresin, such that adsorption of large proteins and platelets is preventedand activation of blood complement system is minimized without blockingaccess by blood toxicants to the inner adsorption space of the resin forsmall and middle-size toxicant molecules. Preparation of the polymericresin beads useful for this invention may follow known methods ofaddition polymerization. Helfferich. F., Ion Exchange, McGraw-Hill BookCompany, Inc., 1962, p. 34-36 to produce resin heads of known sizes: 25to 2500 μm, preferably from 50 to 1500 μm.

As monomeric starting materials for preparation of the inventivepolymeric resin, divinylbenzene (DVB) is the preferred material. Asnoted by Helfferich, pure divinylbenzene is not readily accessible.Commercially available sources are mixtures of divinylbenzene isomers(about 40 to 60 percent) and ethylstyrene (about 60 to 40 percent).Nominal DVB content is referenced as the mole percent of puredivinylbenzene monomer in the polymerization starting materials. Themonomeric starting materials are combined with an addition type catalystsuch as benzoyl peroxide, lauroyl peroxide, t-butyl hydroperoxide, orasobisisobutyronitrile present from 0.5 to 5 percent by weight of themonomeric reactants present. The hydrophobic monomeric startingmaterials are formed into small droplets, such as by agitation in waterto which a suspension stabilizer such as: geletin, polyvinyl alcohol, anoleate salt, or a methacrylate salt has been added. The aqueous phaseincluding the droplets of catalyzed monomer of DVB and divinylbenzeneare maintained at a temperature (40 to 110° C., preferably from 60 to90° C.) sufficient for polymerization. Of course pressurization will benecessary to polymerize the monomers in liquid water at temperaturesgreater than 100° C. Alternatively, the beads can be externally sized inorder to provide a more narrow particle size distribution as describedin U.S. Pat. No. 4,444,961, incorporated herein by reference.

In contrast to the polymeric resin of U.S. Pat. Nos. 5,773,384 and5,051,185, according to the instant invention resin isformed frommonomeric starting materials comprising DVB of 40 percent or more.Further, is not necessary or desirable to subject the resin to a solventswelling and subsequent cross-linking step with a Lewis acid catalyst.Rather, DVB resin can be prepared with porosity suitable for absorbingthe contaminants in blood by variation of the known parameters forpreparation of DVB resins: temperature, solvent amount and choice ofcatalyst, and reaction time. Upgrading of the DVB monomer fromcommercially available values to 65 to 90 mole % DVB can provide theskilled artisan another parameter useful to benefit pore size, porosity,and surface area.

Rendering DVB resin hemocompatible also varies from the prior art ofU.S. Pat. No. 5,773,384. Several approaches to chemically modify thebead surface of an adsorbent are suggested to render the resinhemocompatibile. These approaches include: the formation of lipid-likelayers on the surface of polystyrene beads in an attempt to simulate thestructure of biomembranes by forming co-polymers of2-methacryloyloxyethyl-phosphorylcholine with n-butylmethacrylategrafted on the surface of a polystyrene resin. Groups ofphosphatidylcholine are formed on the surface of polystyrene beads,without a preliminary grafting of the hydrophilic copolymer suggested byIshihara, et al. Secondly, heparin deposited on the surface of thepolystyrene beads are believed to inhibit activation of the bloodcomplement system and prevent formation of clots. Thirdly, longhydrophilic polymer chains on the surface are believed to preventcontacts between blood proteins and cells with the hydrophobicpolystyrene surface. A fourth approach is to deposit high molecularweight fluorinated polyalkoxyphosphazene on the outer surface of thebeads.

All the forgoing methods of rendering hemocompatible the cross-linkedpolystyrene resin require the presence of unreacted functional groupsremaining after crosslinking polystyrene chains with large amounts ofbifunctional compounds, in particular, those bearing reactivechloromethyl groups. This process is limited to a curiosity as it is notscaleable to commercial size manufacture. In contrast, porous adsorbentprepared from divinylbenzene is not only commercially scaleable, butsuch resins are presently available. Suitable commercially availableresins include Dowex® polymeric resins available from The Dow ChemicalCompany, Midland, Mich., United States of America identified as Dowexproduct numbers XUS-43520.01, XUS-43520.10, and XUS-40323.00.

In contrast to the polystyrene resins mildly cross-linked with amountsof DVB disclosed from 0.5 to 4.5 percent having negligible unreactedvinyl groups taught by U.S. Pat. No. 5,773,384 which polystyrene resinsmust be subsequently cross-linked with bi-functional cross-linkers suchas dichlorodimethyl ether, the DVB resins of the instant invention arereadily rendered hemocompatible by coating the resin by reaction ofvinyl reactive and hemocompatible monomers and polymers with unreactedvinyl groups of the DVB resins. Also in contrast to the water-insolublecarrier of particulate or spherical form according to U.S. Pat. No.5,051,185, the inventive resins while having a surface area from 20 to500 m²/g, a pore size from 20 to 500 Å, preferably from 20 to 300 Å, anda pore volume less than 2.5 cc/g, preferably less than 2.0 cc/g, butmore than 1.0 cc/g, the instant resins can be manufactured having asurface area from 200 to 1,600 m²/g, preferably from 500 to 1,200 m²/g,more preferably 700 to 1,000 m²/g.

Suitable hemocompatible coating may be prepared from a wide variety ofsuch reactants capable of reacting with vinyl groups. Suitable nitrogencontaining reactants include: primary amines, secondary amines, tertiaryamines, quaternary amines and nitrogen-containing aromatic cycliccompounds such as pyridines, and imidazols. Specific examples ofaromatic cyclic compounds include vinyl derivatives of such nitrogencontaining compounds such as 2-vinylpyridine, 4-vinylpyridine,2-methyl-5-vinylpyridine, 4-vinylimidazole, N-vinyl-2-ethylimidazole,vinylpyrrolidinone, N-vinyl-2-methylimidazole. Also useful are acrylicor (meth)acrylic acid derivatives including: dimethylaminoethyl(meth)acrylate, diethylaminoethyl (meth)acrylate, dimethylaminopropyl(meth)acrylate, 3-dimethylamino-2-hydroxypropyl (meth)acrylate),acrylamide or methacrylamide derivative. Acrylamide and methacrylamidesuch as N-dimethylaminoethyl (meth)acrylamide, N-diethylaminoethyl(meth)acrylamide. Useful alone, or as a co-polymer with the abovementioned addition polymerizable nitrogen containing monomers, are thealkyl (meth)acrylates i.e., 2-hydroxyethyl methacrylate, methyl(meth)acrylate, ethyl (meth)acrylate, and n-butyl(meth)acrylate. Alsouseful alone or as a co-polymer as a hemocompatible coating are N-methyl(meth)acrylamide, N-vinylpyrrolidone, vinyl acetate, and vinylpyridine.

Reaction conditions for coating the DVB resin beads with a vinylreactive additive reactant are similar to the reaction conditions forformation of the DVB resin: a suitable catalyst such as are generallyknown, a suitable solvent, heating the DVB resin, catalyst, solvent, andadditive reactant to the reactive temperature: generally from 40 to 110°C., for a time sufficient for reaction, from 8 hours to ½ hour.

By rendering such resins hemocompatible, effective adsorbents for bloodtoxins can be provided. Such divinylbenzene resins avoid cross-linkingof styrene-divinylbenzene copolymers with monochlorodimethyl ether as abifunctional reagent, or cross-linking of such resin usingchloromethylation taught by U.S. Pat. No. 5,773,384. Consequently, theconcerns for removing unreacted cross-linker can be avoided.

The adsorbents prepared in accordance with this invention are charged toa column or cartridge for use to removal contaminants from blood orplasma. The column should preferably be provided with an inlet and anoutlet designed to allow easy connection with the blood circuit, andwith two porous filters set between the inlet and the absorbent layer,and between the absorbent layer and the outlet. The column may be madeof a biocompatible material, glass, polyethylene, polypropylene,polycarbonate polystyrene. Of these, polypropylene and polycarbonate arepreferred materials, because the column packed with the sorbent can besterilized (e.g., autoclave and alpha-ray sterilization) before use.

By adjusting the pore size of the DVB resin and rendering the resinhemocompatible, the resin is useful to remove blood components havingmolecular weights of between 100 and 20,000 daltons including proteins,glycosated proteins, including degranulation inhibitory protein,advanced glycosylation endproducts, hormones such as parathyroid hormoneand endotoxins such as those toxins which cause sepsis. Such compoundsas creatinine, barbiturate, phenobarbital, sodium salicylate,amphetamines, morphine sulfate, meprobamate, glutethimide, etc. can alsobe effectively and rapidly removed from the blood by the disclosed resinrendered hemocompatible. Moreover, by adjusting the reaction conditionsas stated herein to generate proper pore sizes, the hemocompatible resinwill absorb cytochrome C, β-2-microglobulin (molecular weight of about20,000 daltons), as well as vitamin B₁₂.

EXAMPLE 1

Divinylbenzene/ethyl vinylbenzene copolymer beads having a ratio of DVBto EVB of 80 to 20 on a weight basis were dried at 70° C. in a vacuumoven for 24 hours. 100 g of the resulting beads were placed into a flaskwith 650 ml of methanol. The reaction mixture was heated to 65° C. andthis temperature maintained until 200 ml of distillate removed. 200 mlmethanol was then added to the flask. After cooling to ambienttemperature, 1-vinyl-2-pyrrolidinone (1.0 g., 9.0 mMole) and 75 ml ofmethanol is added followed by 0.237 g. (0.9 mMole) of α-cumylperoxyneoheptanoate and 20 ml methanol, followed by heating to 64° C.for 4 hours while stirring gently. The solvent is removed from the resinbeads by suction filtration. The beads were rinsed with 400 ml methanol,followed by washing by 1 L methanol in a column with methanol pumpedthrough the column at a rate of 3 ml/min.

EXAMPLE 2

Divinylbenzene/ethyl vinylbenzene copolymer beads having a ratio of DVBto EVB of 80 to 20 on a weight basis were dried at 70° C. in a vacuumoven for 24 hours. 100 g of the resulting beads were placed into a flaskwith 650 ml of ethanol. The reaction mixture was heated to 78° C. andthis temperature maintained until 200 ml of distillate removed. 200 mlethanol was then added to the flask. After cooling to ambienttemperature, polyvinyl pyrrolidinone molecular weight, 10,000 (1.0 g.,9.0 mMole) available from Aldrich P.O. 2060 Milwaukee Wis. 53201 UnitedStates solid was added, followed by 0.02 g. (0.18 mMole) of α-cumylperoxyneoheptanoate, followed by heating to 78° C. for 4 hours whilestirring gently. The solvent was removed from the resin beads by suctionfiltration. The beads were rinsed with 400 ml ethanol, followed bywashing by 1 L ethanol in a column pumped through the column at a rateof 3 ml/min for 5.5 hours followed by a wash of 1 L of 2-propanol pumpedthrough the column at a rate of 3 ml/min for 5.5 hours.

The polymer beads when contacted with blood are compatible. Blood doesnot clot on contact. The beads remove blood contaminants such asβ-2-microglobulin.

What is claimed is:
 1. A polymeric divinylbenzene resin, comprising from60 to 90 mole percent divinylbenzene having a hemocompatible coating onthe surface thereof.
 2. The resin of claim 1 comprising from 65 to 90mole percent divinylbenzene.
 3. The resin of claim 1 comprising from 60to 80 mole percent divinylbenzene.
 4. The resin of claim 1 comprisingabout 80 mole percent divinylbenzene.
 5. The resin of claim 1 whereinthe surface of the resin is rendered hemocompatible through reaction ofvinyl reactive hemocompatible monomers or polymers with unreacted vinylgroups of the resin.
 6. The resin according to claim 1, wherein thehemocompatible coating is selected from the group consisting ofphosphatidylcholine, heparin, polyalkylene glycol,polyalkoxyphosphazene, and polyvinylpyrrolindone.
 7. The resin accordingto claim 1, wherein the hemocompatible coating is selected from thegroup consisting of 2-vinylpyridine, 4-vinylpyridine,2-methyl-5-vinylpyridine, 4-vinylimidazole, N-vinyl-2-ethylimidazole,vinylpyrrolidone, and N-vinyl-2-methylimidazole.
 8. The resin accordingto claim 1, wherein the hemocompatible coating is selected from thegroup consisting of acrylic and methacrylic acid derivatives including:dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate,dimethylaminopropyl (meth)acrylate, and 3-dimethylamino-2-hydroxypropyl(meth)acrylate); acrylamide and methacrylamide derivative; acrylamideand methacrylamide including N-dimethylaminoethyl (meth)acrylamide,N-diethylaminoethyl (meth)acrylamide.
 9. The resin according to claim 1,wherein the hemocompatible coating is an alkyl (meth)acrylate selectedfrom the group consisting of 2-hydroxyethyl methacrylate, methyl(meth)acrylate, ethyl (meth)acrylate, and n-butyl(meth)acrylate.
 10. Theresin according to claim 1, wherein the hemocompatible coating isselected from the group consisting of N-methyl (meth)acrylamide,N-vinylpyrrolidone, vinyl acetate, and vinylpyridine.
 11. The resinaccording to claim 1 in the form of beads having a size from 25 to 2500μm.
 12. The resin according to claim 1 wherein the resin has a pore sizefrom 20 to 500 Å.
 13. The resin according to claim 1 wherein the resinhas a pore volume less that 2.5 cc/g.
 14. The resin according to claim 1wherein the resin has a surface area from 200 to 1600 m²/g.
 15. Theresin of claim 12 wherein the resin has a pore volume of less than 2.5cc/g.
 16. The resin of claim 15 wherein the resin has a surface areafrom 200 to 1600 m²/g.
 17. The resin according to claim 1 wherein thehemocompatible coating is a polymer prepared from the group consisting2-hydroxyethyl methacrylate, methyl(meth)acrylate, ethyl(meth)acrylate,n-butyl (meth)acrylate, and vinylpyrrolidone.
 18. A polymericdivinylbenzene resin comprising from greater than 50 to less than 90mole percent divinylbenzene having a hemocompatible coating on thesurface thereof.
 19. The resin of claim 18 comprising from 60 to 80 molepercent divinylbenzene.
 20. The resin of claim 18 wherein the surface ofthe resin is rendered hemocompatible through reaction of vinyl reactivehemocompatible monomers or polymers with unreacted vinyl groups of theresin.
 21. The resin according to claim 20 wherein the hemocompatiblecoating is selected from the group consisting of phosphatidylcholine,heparin, polyalkylene glycol, polyalkoxyphosphazene, andpolyvinylpyrrolindone.
 22. The resin according to claim 20 wherein thehemocompatible coating is selected from the group consisting of2-vinylpyridine, 4-vinylpyridine, 2-methyl-5-vinylpyridine,4-vinylimidazole, N-vinyl-2-ethylimidazole, vinylpyrrolidone, andN-vinyl-2-methylimidazole.
 23. The resin according to claim 20 whereinthe hemocompatible coating is selected from the group consisting ofacrylic and methacrylic acid derivatives including: dimethylaminoethyl(meth)acrylate, diethylaminoethyl (meth)acrylate, dimethylaminopropyl(meth)acrylate, and 3-dimethylamino-2-hydroxypropyl (meth)acrylate);acrylamide and methacrylamide derivative; acrylamide and methacrylamideincluding N-dimethylaminoethyl (meth)acrylamide, N-diethylaminoethyl(meth)acrylamide.
 24. The resin according to claim 20 wherein thehemocompatible coating is an alkyl (meth)acrylate selected from thegroup consisting of 2-hydroxyethyl methacrylate, methyl (meth)acrylate,ethyl (meth)acrylate, and n-butyl(meth)acrylate.
 25. The resin accordingto claim 20 wherein the hemocompatible coating is selected from thegroup consisting of N-methyl (meth)acrylamide, N-vinylpyrrolidone, vinylacetate, and vinylpyridine.
 26. The resin according to claim 20 in theform of beads having: a size from 25 to 2500 μm, a pore size from 20 to500 Å, a pore volume less that 2.5 cc/g, and a surface area from 200 to1600 m²/g.